P47973 · TTP_RAT

  • Protein
    mRNA decay activator protein ZFP36
  • Gene
    Zfp36
  • Status
    UniProtKB reviewed (Swiss-Prot)
  • Amino acids
  • Protein existence
    Evidence at protein level
  • Annotation score
    5/5

Function

function

Zinc-finger RNA-binding protein that destabilizes numerous cytoplasmic AU-rich element (ARE)-containing mRNA transcripts by promoting their poly(A) tail removal or deadenylation, and hence provide a mechanism for attenuating protein synthesis (PubMed:27193233).
Acts as an 3'-untranslated region (UTR) ARE mRNA-binding adapter protein to communicate signaling events to the mRNA decay machinery. Recruits deadenylase CNOT7 (and probably the CCR4-NOT complex) via association with CNOT1, and hence promotes ARE-mediated mRNA deadenylation. Functions also by recruiting components of the cytoplasmic RNA decay machinery to the bound ARE-containing mRNAs. Self regulates by destabilizing its own mRNA (By similarity).
Binds to 3'-UTR ARE of numerous mRNAs (PubMed:27193233).
Binds also to ARE of its own mRNA. Plays a role in anti-inflammatory responses; suppresses tumor necrosis factor (TNF)-alpha production by stimulating ARE-mediated TNF-alpha mRNA decay and several other inflammatory ARE-containing mRNAs in interferon (IFN)- and/or lipopolysaccharide (LPS)-induced macrophages. Also plays a role in the regulation of dendritic cell maturation at the post-transcriptional level, and hence operates as part of a negative feedback loop to limit the inflammatory response. Promotes ARE-mediated mRNA decay of hypoxia-inducible factor HIF1A mRNA during the response of endothelial cells to hypoxia. Positively regulates early adipogenesis of preadipocytes by promoting ARE-mediated mRNA decay of immediate early genes (IEGs). Negatively regulates hematopoietic/erythroid cell differentiation by promoting ARE-mediated mRNA decay of the transcription factor STAT5B mRNA. Plays a role in maintaining skeletal muscle satellite cell quiescence by promoting ARE-mediated mRNA decay of the myogenic determination factor MYOD1 mRNA. Associates also with and regulates the expression of non-ARE-containing target mRNAs at the post-transcriptional level, such as MHC class I mRNAs. Participates in association with argonaute RISC catalytic components in the ARE-mediated mRNA decay mechanism; assists microRNA (miRNA) targeting ARE-containing mRNAs. May also play a role in the regulation of cytoplasmic mRNA decapping; enhances decapping of ARE-containing RNAs, in vitro. Involved in the delivery of target ARE-mRNAs to processing bodies (PBs). In addition to its cytosolic mRNA-decay function, affects nuclear pre-mRNA processing. Negatively regulates nuclear poly(A)-binding protein PABPN1-stimulated polyadenylation activity on ARE-containing pre-mRNA during LPS-stimulated macrophages. Also involved in the regulation of stress granule (SG) and P-body (PB) formation and fusion. Plays a role in the regulation of keratinocyte proliferation, differentiation and apoptosis. Plays a role as a tumor suppressor by inhibiting cell proliferation in breast cancer cells (By similarity).

GO annotations

AspectTerm
Cellular ComponentCCR4-NOT complex
Cellular Componentcytoplasm
Cellular Componentcytoplasmic stress granule
Cellular Componentcytosol
Cellular Componentnucleus
Cellular ComponentP-body
Cellular Componentribonucleoprotein complex
Molecular Function14-3-3 protein binding
Molecular FunctionC-C chemokine binding
Molecular FunctionDNA binding
Molecular Functionenzyme binding
Molecular Functionheat shock protein binding
Molecular Functionmetal ion binding
Molecular FunctionmRNA 3'-UTR AU-rich region binding
Molecular FunctionmRNA 3'-UTR binding
Molecular FunctionmRNA binding
Molecular Functionprotein kinase binding
Molecular Functionprotein-containing complex binding
Molecular FunctionRNA polymerase binding
Biological Process3'-UTR-mediated mRNA destabilization
Biological Process3'-UTR-mediated mRNA stabilization
Biological Processcellular response to epidermal growth factor stimulus
Biological Processcellular response to fibroblast growth factor stimulus
Biological Processcellular response to glucocorticoid stimulus
Biological Processcellular response to granulocyte macrophage colony-stimulating factor stimulus
Biological Processcellular response to lipopolysaccharide
Biological Processcellular response to tumor necrosis factor
Biological Processhematopoietic stem cell differentiation
Biological Processintracellular signal transduction
Biological ProcessMAPK cascade
Biological ProcessmiRNA-mediated gene silencing by inhibition of translation
Biological ProcessmRNA catabolic process
Biological ProcessmRNA transport
Biological Processmyeloid cell differentiation
Biological Processnegative regulation of erythrocyte differentiation
Biological Processnegative regulation of hematopoietic stem cell differentiation
Biological Processnegative regulation of inflammatory response
Biological Processnegative regulation of interleukin-2 production
Biological Processnegative regulation of myeloid cell differentiation
Biological Processnegative regulation of polynucleotide adenylyltransferase activity
Biological Processnegative regulation of transcription by RNA polymerase II
Biological Processnegative regulation of viral transcription
Biological Processnuclear-transcribed mRNA catabolic process, deadenylation-dependent decay
Biological Processnuclear-transcribed mRNA catabolic process, deadenylation-independent decay
Biological Processnuclear-transcribed mRNA poly(A) tail shortening
Biological Processp38MAPK cascade
Biological Processpositive regulation of deadenylation-independent decapping of nuclear-transcribed mRNA
Biological Processpositive regulation of fat cell differentiation
Biological Processpositive regulation of intracellular mRNA localization
Biological Processpositive regulation of miRNA-mediated gene silencing
Biological Processpositive regulation of mRNA catabolic process
Biological Processpositive regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay
Biological Processpositive regulation of nuclear-transcribed mRNA poly(A) tail shortening
Biological Processregulation of keratinocyte apoptotic process
Biological Processregulation of keratinocyte differentiation
Biological Processregulation of keratinocyte proliferation
Biological Processregulation of mRNA stability
Biological Processregulation of transcription by RNA polymerase II
Biological Processregulation of tumor necrosis factor production
Biological Processresponse to starvation
Biological Processresponse to wounding
Biological ProcessRNA destabilization

Keywords

Enzyme and pathway databases

Names & Taxonomy

Protein names

  • Recommended name
    mRNA decay activator protein ZFP36
  • Alternative names
    • TPA-induced sequence 11
    • Tristetraprolin
    • Zinc finger protein 36
      (Zfp-36
      )

Gene names

    • Name
      Zfp36
    • Synonyms
      Tis11
      , Ttp

Organism names

  • Taxonomic identifier
  • Taxonomic lineage
    Eukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Glires > Rodentia > Myomorpha > Muroidea > Muridae > Murinae > Rattus

Accessions

  • Primary accession
    P47973
  • Secondary accessions
    • Q54AH1

Proteomes

Organism-specific databases

Subcellular Location

Nucleus
Cytoplasm
Cytoplasmic granule
Cytoplasm, P-body
Note: Shuttles between nucleus and cytoplasm in a CRM1-dependent manner (PubMed:12054509).
Localized predominantly in the cytoplasm in a p38 MAPK- and YWHAB-dependent manner. Colocalizes with SH3KBP1 and MAP3K4 in the cytoplasm. Component of cytoplasmic stress granules (SGs). Localizes to cytoplasmic stress granules upon energy starvation. Localizes in processing bodies (PBs). Excluded from stress granules in a phosphorylation MAPKAPK2-dependent manner. Shuttles in and out of both cytoplasmic P-body and SGs (By similarity).

Keywords

Phenotypes & Variants

Features

Showing features for mutagenesis.

TypeIDPosition(s)Description
Mutagenesis3Inhibits nucleus export.
Mutagenesis10Inhibits nucleus export.

PTM/Processing

Features

Showing features for chain, modified residue.

TypeIDPosition(s)Description
ChainPRO_00000891651-320mRNA decay activator protein ZFP36
Modified residue53Phosphoserine; by MAPKAPK2
Modified residue59Phosphoserine
Modified residue81Phosphoserine
Modified residue83Phosphoserine
Modified residue85Phosphothreonine
Modified residue86Phosphoserine
Modified residue179Phosphoserine; by MAPKAPK2
Modified residue190Phosphoserine
Modified residue211Phosphoserine
Modified residue221Phosphoserine; by MAPK1; in vitro
Modified residue251Phosphothreonine
Modified residue270Phosphoserine
Modified residue290Phosphoserine
Modified residue317Phosphoserine

Post-translational modification

Phosphorylated. Phosphorylation at serine and/or threonine residues occurs in a p38 MAPK- and MAPKAPK2-dependent manner. Phosphorylated by MAPKAPK2 at Ser-53 and Ser-179; phosphorylation increases its stability and cytoplasmic localization, promotes binding to 14-3-3 adapter proteins and inhibits the recruitment of cytoplasmic CCR4-NOT and PAN2-PAN3 deadenylase complexes to the mRNA decay machinery, thereby inhibiting ZFP36-induced ARE-containing mRNA deadenylation and decay processes. Phosphorylation by MAPKAPK2 does not impair ARE-containing RNA-binding. Phosphorylated in a MAPKAPK2- and p38 MAPK-dependent manner upon skeletal muscle satellite cell activation; this phosphorylation inhibits ZFP36-mediated mRNA decay activity, and hence stabilizes MYOD1 mRNA. Phosphorylated by MAPK1 upon mitogen stimulation. Phosphorylated at Ser-59 and Ser-86; these phosphorylations increase in a SH3KBP1-dependent manner. Phosphorylated at serine and threonine residues in a pyruvate kinase PKM- and p38 MAPK-dependent manner. Phosphorylation at Ser-53 may participate in the PKM-mediated degradation of ZFP36 in a p38 MAPK-dependent manner. Dephosphorylated by serine/threonine phosphatase 2A at Ser-179.
Ubiquitinated; pyruvate kinase (PKM)-dependent ubiquitination leads to proteasomal degradation through a p38 MAPK signaling pathway.

Keywords

Proteomic databases

PTM databases

Interaction

Subunit

Associates with cytoplasmic CCR4-NOT and PAN2-PAN3 deadenylase complexes to trigger ARE-containing mRNA deadenylation and decay processes. Part of a mRNA decay activation complex at least composed of poly(A)-specific exoribonucleases CNOT6, EXOSC2 and XRN1 and mRNA-decapping enzymes DCP1A and DCP2. Associates with the RNA exosome complex. Interacts (via phosphorylated form) with 14-3-3 proteins; these interactions promote exclusion of ZFP36 from cytoplasmic stress granules in response to arsenite treatment in a MAPKAPK2-dependent manner and does not prevent CCR4-NOT deadenylase complex recruitment or ZFP36-induced ARE-containing mRNA deadenylation and decay processes. Interacts with 14-3-3 proteins; these interactions occur in response to rapamycin in an Akt-dependent manner. Interacts with AGO2 and AGO4. Interacts (via C-terminus) with CNOT1; this interaction occurs in a RNA-independent manner and induces mRNA deadenylation. Interacts (via N-terminus) with CNOT6. Interacts with CNOT6L. Interacts (via C-terminus) with CNOT7; this interaction occurs in a RNA-independent manner, induces mRNA deadenylation and is inhibited in a phosphorylation MAPKAPK2-dependent manner. Interacts (via unphosphorylated form) with CNOT8; this interaction occurs in a RNA-independent manner and is inhibited in a phosphorylation MAPKAPK2-dependent manner. Interacts with DCP1A. Interacts (via N-terminus) with DCP2. Interacts with EDC3. Interacts (via N-terminus) with EXOSC2. Interacts with heat shock 70 kDa proteins. Interacts with KHSRP; this interaction increases upon cytokine-induced treatment. Interacts with MAP3K4; this interaction enhances the association with SH3KBP1/CIN85. Interacts with MAPKAPK2; this interaction occurs upon skeletal muscle satellite cell activation. Interacts with NCL. Interacts with NUP214; this interaction increases upon lipopolysaccharide (LPS) stimulation. Interacts with PABPC1; this interaction occurs in a RNA-dependent manner. Interacts (via hypophosphorylated form) with PABPN1 (via RRM domain and C-terminal arginine-rich region); this interaction occurs in the nucleus in a RNA-independent manner, decreases in presence of single-stranded poly(A) RNA-oligomer and in a p38 MAPK-dependent-manner and inhibits nuclear poly(A) tail synthesis. Interacts with PAN2. Interacts (via C3H1-type zinc finger domains) with PKM. Interacts (via C3H1-type zinc finger domains) with nuclear RNA poly(A) polymerase. Interacts with PPP2CA; this interaction occurs in LPS-stimulated cells and induces ZFP36 dephosphorylation, and hence may promote ARE-containing mRNAs decay. Interacts (via C-terminus) with PRR5L (via C-terminus); this interaction may accelerate ZFP36-mediated mRNA decay during stress. Interacts (via C-terminus) with SFN; this interaction occurs in a phosphorylation-dependent manner. Interacts (via extreme C-terminal region) with SH3KBP1/CIN85 (via SH3 domains); this interaction enhances MAP3K4-induced phosphorylation of ZFP36 at Ser-59 and Ser-86 and does not alter neither ZFP36 binding to ARE-containing transcripts nor TNF-alpha mRNA decay. Interacts with XRN1. Interacts (via C-terminus and Ser-179 phosphorylated form) with YWHAB; this interaction occurs in a p38/MAPKAPK2-dependent manner, increases cytoplasmic localization of ZFP36 and protects ZFP36 from Ser-179 dephosphorylation by serine/threonine phosphatase 2A, and hence may be crucial for stabilizing ARE-containing mRNAs. Interacts (via phosphorylated form) with YWHAE. Interacts (via C-terminus) with YWHAG; this interaction occurs in a phosphorylation-dependent manner. Interacts with YWHAH; this interaction occurs in a phosphorylation-dependent manner. Interacts with YWHAQ; this interaction occurs in a phosphorylation-dependent manner. Interacts with (via C-terminus) YWHAZ; this interaction occurs in a phosphorylation-dependent manner. Does not interact with SH3KBP1. Interacts (via P-P-P-P-G repeats) with GIGYF2; the interaction is direct (By similarity).

Protein-protein interaction databases

Structure

Family & Domains

Features

Showing features for region, compositional bias, repeat, zinc finger.

TypeIDPosition(s)Description
Region1-15Necessary for nuclear export
Region1-93Necessary and sufficient for the association with mRNA decay enzymes and mRNA decay activation
Region1-167Necessary for localization of ARE-containing mRNAs to processing bodies (PBs)
Region17-50Disordered
Compositional bias19-50Polar residues
Repeat64-68P-P-P-P-G
Compositional bias66-85Pro residues
Region66-95Disordered
Region88-161Necessary for nuclear localization
Region90-166Necessary for RNA-binding
Region93-320Necessary for localization of ARE-containing mRNAs to processing bodies (PBs)
Zinc finger96-124C3H1-type 1
Region96-187Necessary for interaction with PABPN1
Zinc finger134-162C3H1-type 2
Region167-320Necessary for mRNA decay activation
Region180-310Disordered
Repeat191-195P-P-P-P-G
Repeat212-216P-P-P-P-G
Compositional bias274-288Polar residues
Region306-320Interaction with CNOT1

Domain

The C3H1-type zinc finger domains are necessary for ARE-binding activity.

Keywords

Phylogenomic databases

Family and domain databases

Sequence

  • Sequence status
    Complete
  • Length
    320
  • Mass (Da)
    33,654
  • Last updated
    1996-10-01 v1
  • Checksum
    CFC597F3C7E5CA76
MDLSAIYESLMSMSHDLSPDHGGTESSGGLWNINSSDSIPSGVTSRLTGRSTSLVEGRSCSWVPPPPGFAPLAPRPGPELSPSPTSPTATPTTSSRYKTELCRTYSESGRCRYGAKCQFAHGPGELRQANRHPKYKTELCHKFYLQGRCPYGSRCHFIHNPTEDLALPGQPHVLRQSISFSGLPSGRRTSPPPPGFSGPSLSSCSFSPSSSPPPPGDLPLSPSAFSAAPGTPVSRRDPTPACCPSCRRSTTPSTIWGPLGGLARSPSAHSLGSDPDDYASSGSSLGGSDSPVFEAGVFGPPQPPAPPRRLPIFNRISVSE

Computationally mapped potential isoform sequences

There is 1 potential isoform mapped to this entry

View all
EntryEntry nameGene nameLength
G3V8K6G3V8K6_RATZfp36326

Features

Showing features for compositional bias.

TypeIDPosition(s)Description
Compositional bias19-50Polar residues
Compositional bias66-85Pro residues
Compositional bias274-288Polar residues

Keywords

Sequence databases

Nucleotide SequenceProtein SequenceMolecule TypeStatus
X63369
EMBL· GenBank· DDBJ
CAA44970.1
EMBL· GenBank· DDBJ
mRNA
AB025017
EMBL· GenBank· DDBJ
BAB12432.1
EMBL· GenBank· DDBJ
Genomic DNA
BC060308
EMBL· GenBank· DDBJ
AAH60308.1
EMBL· GenBank· DDBJ
mRNA

Genome annotation databases

Similar Proteins

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